title: Xenobiotic metabolism and disposition in human lung: transcript profiling in non-tumoral and tumoral tissues.
abstract: The lung is directly exposed to a wide variety of inhaled toxicants and carcinogens. In order to improve our knowledge of the cellular processing of these compounds in the respiratory tract, we investigated the mRNA expression level of 380 genes encoding xenobiotic-metabolizing enzymes (XME), transporters, nuclear receptors and transcription factors, in pulmonary parenchyma (PP), bronchial mucosa (BM) and tumoral lung tissues from 12 patients with non-small cell lung cancer (NSCLC). Using a high throughput quantitative real-time RT-PCR method, we found that ADH1B, CYP4B1, CES1 and GSTP1 are the major XME genes expressed both in BM and PP. Our results also documented the predominant role played by the xenosensor AhR in human lung. The gene expression profiles were different for BM and PP, with a tendency toward increased mRNA levels of phase I and phase II XME genes in BM, suggesting major differences in the initial stages of xenobiotic metabolism. Some of the significantly overexpressed genes in BM (i.e. CYP2F1, CYP2A13, CYP2W1, NQO1…) encode proteins involved in the bioactivation of procarcinogens, pointing out distinct susceptibility to xenobiotics and their toxic effects between these two tissue types. Additionally, interindividual differences in transcript levels observed for some genes may be of genetic origin and may contribute to the variability in response to environmental exposure and, consequently, in the risk of developing lung diseases. A global decrease in gene expression was observed in tumoral specimens. Some of the proteins are involved in the metabolism or transport of anti-cancer drugs and their influence in the response of tumors to chemotherapy should be considered. In conclusion, the present study provides an overview of the cellular response to toxicants and drugs in healthy and cancerous human lung tissues, and thus improves our understanding of the mechanisms of chemical carcinogenesis as well as cellular resistance to chemotherapy.
authors.affiliation: Equipe d'accueil EA4483, Faculté de Médecine Pôle Recherche, Université Lille Nord de France, 1 Place de Verdun, 59045 Lille, France. julie.leclerc-2@univ-lille2.fr
authors.forename: Julie
authors.initials: J
authors.lastname: Leclerc
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Courcot-Ngoubo Ngangue
authors.forename: Christelle
authors.initials: C
authors.lastname: Cauffiez
authors.forename: Delphine
authors.initials: D
authors.lastname: Allorge
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pottier
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lafitte
authors.forename: Michel
authors.initials: M
authors.lastname: Debaert
authors.forename: Sophie
authors.initials: S
authors.lastname: Jaillard
authors.forename: Franck
authors.initials: F
authors.lastname: Broly
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lo-Guidice
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000368:Aged; D001980:Bronchi / Q000201:enzymology / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009928:Organ Specificity; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000201:enzymology / Q000378:metabolism; D012137:Respiratory System / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D026901:Membrane Transport Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System